Synthesis and transformations of 1-(azidophenyl)-1H-tetrazoles

Article abstract of DOI:10.1134/S1070428010040196

Diazotization of 1-(aminophenyl)-1H-tetrazoles and subsequent treatment of the diazonium salts with sodium azide gave 1-(azidophenyl)-1H-tetrazoles which were brought into cyclization with ethyl acetoacetate and cyanoacetanilide to obtain 1,2,3-triazole derivatives. Under these conditions, the tetrazole ring may undergo cleavage with formation of cyanamide group.

Full text of DOI:10.1134/S1070428010040196

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 4, pp. 556–560. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © N.T. Pokhodylo, V.S. Matiichuk, N.D. Obushak, 2010, published in Zhurnal Organicheskoi Khimii, 2010, Vol. 46, No. 4,
pp. 565–568.
Synthesis and Transformations of 1-(Azidophenyl)-1H-tetrazoles
N. T. Pokhodylo, V. S. Matiichuk, and N. D. Obushak
Ivan Franko Lviv National University, ul. Kirilla i Mefodiya 6, Lviv, 79005 Ukraine
e-mail: obushak@in.lviv.ua
Received May 25, 2009
Abstract—Diazotization of 1-(aminophenyl)-1H-tetrazoles and subsequent treatment of the diazonium salts
with sodium azide gave 1-(azidophenyl)-1H-tetrazoles which were brought into cyclization with ethyl aceto-
acetate and cyanoacetanilide to obtain 1,2,3-triazole derivatives. Under these conditions, the tetrazole ring may
undergo cleavage with formation of cyanamide group.
DOI: 10.1134/S1070428010040196
5-Substituted tetrazoles are the most thoroughly
studied tetrazole derivatives, for they are readily avail-
able via 1,3-dipolar cycloaddition of azides to nitriles.
2- and 1-Substituted tetrazoles have been studied to
a lesser extent [1–3]. 1-Substituted tetrazoles became
more accessible due to development of a procedure for
their preparation by reaction of amines with triethyl
orthoformate and sodium azide [4, 5]. This reaction
was used to synthesize with high yields tetrazoles
having various substituents in position 1 [3–7]. Some
1-substituted tetrazoles were found to exhibit bio-
logical activity [8, 9] and complexing ability toward
various metals [10–12]. For example, tetrazoles were
used as ligands in palladium-catalyzed Suzuki
reactions [13].
of structurally related tetrazolylphenyltriazoles attracts
interest from the viewpoint of practice.
As starting compounds we used nitroanilines Ia and
Ib which were converted in two steps into tetrazolyl-
anilines IIIa and IIIb. Compounds IIIa and IIIb were
previously synthesized by reduction of the correspond-
ing nitroaryltetrazoles [11]. The use of tin(II) chloride
instead of metallic iron allowed us to raise the yield
and reduce the probability for cleavage of the tetrazole
ring. 4-(1H-Tetrazol-1-yl)aniline (IIIb) was also syn-
thesized starting from p-phenylenediamine whose acet-
ylation gave N-(4-aminophenyl)acetamide (Ic). The
free amino group in the latter was converted into tetra-
zole ring, and removal of the acetyl protection from
compound II afforded compound IIIb (Scheme 1).
However, chemical behavior of 1-substituted tetra-
zoles was studied poorly. Insofar as the tetrazole ring is
not very stable, its behavior in various reactions is
often unpredictable, and it was not studied. In partic-
ular, tetrazole ring is not stable in strongly basic
medium. Vorobiov et al. [14] described one-pot syn-
thesis of 5-aminotetrazoles via decomposition of tetra-
zoles and subsequent cyclization of the cyanamide
group thus formed by the action of sodium azide. We
recently demonstrated prospects in using 1-substituted
tetrazoles as precursors of cyanamides which were
generated in situ by cleavage of tetrazole ring in the
synthesis of 2,3-diaminothieno[2,3-d]pyrimidines [6].
Anilines IIIa and IIIb were subjected to diazotiza-
tion by treatment with sodium nitrite in hydrochloric
acid to obtain stable (in solution) diazonium salts [15].
These diazonium salts were found to arylate methyl
acrylate, furfurol, and furan-2-carboxylic acid under
Meerwein reaction conditions [15]. Treatment of the
diazonium salts with sodium azide gave the corre-
sponding azides Va and Vb. Despite the presence of
many nitrogen atoms in their molecules, 1-(azido-
phenyl)tetrazoles Va and Vb turned out to be fairly
stable. There is an empirical rule according to which
organic azides are safe in handling and nonexplosive
if the number of nitrogen atoms therein (NN) does
not exceed the number of carbon atoms (NC) and
(NC + NO)/NN ≥ 3 [16, 17].
In the present work we tried to find synthetic ap-
proaches to (1H-tetrazol-1-yl)phenyl-1H-1,2,3-triazole
derivatives. Phenylenebis(1H-tetrazoles) are good
complexing agents for copper [11]; therefore, synthesis
Azides Va and Vb were used to construct triazole
ring via cyclization with compounds having an activat-
556

SYNTHESIS AND TRANSFORMATIONS OF 1-(AZIDOPHENYL)-1H-TETRAZOLES
557
Scheme 1.
N
N
N
NaN3, CH(OEt)3
N
AcOH
R = 4-AcNH
AcNH
II
HCl
N
N
(1) NaN3, CH(OEt)3
AcOH
(2) Fe, EtOH, H2O
N
NH2
N
R
H2N
Ia–Ic
IIIa, IIIb
N
O
N
(1) MeC(O)CH2C(O)OEt
EtONa, EtOH
(2) HCl
(1) NaNO2, HCl
(2) NaN3
N3
N
OH
R = 4-AcNH
Me
AcNH
H2N
IV
VIII
N
N
N
O
NaN3, CH(OEt)3, AcOH
N
N
OH
Me
N
N
VIb
MeC(O)CH2C(O)OEt
EtONa, EtOH, 20°C
VIa, VIb
+
KOH, DMSO
20°C
VIIa, VIIb
N
N
N
N
O
N
N
N
N
(1) NaNO2, HCl
(2) NaN3
MeC(O)CH2C(O)OEt
EtONa, EtOH, Δ, 2 h
N
N
N
N
OH
H2N
N3
N
Me
H
N
IIIa, IIIb
Va, Vb
VIIa, VIIb
N
O
N
PhNHC(O)CH2CN
MeONa, MeOH
N
N
N
NHPh
N
IXa, IXb
I, R = 3-O2N (a), 4-O2N (b), 4-AcNH (c); III, V–VII, IX, meta substitution (a), para substitution (b).
ed methylene group in the presence of bases. The
reactions of azides Va and Vb with ethylacetoacetate
at room temperature gave mixtures of expected cy-
clization products VIa and VIb and cyanamides VIIa
and VIIb, the latter being formed as a result of cleav-
age of the tetrazole ring. To ensure complete hydrol-
ysis of the ester group, the reaction mixtures were
heated to the boiling point and treated with water.
Under these conditions, complete decomposition of the
tetrazole ring occurred with elimination of nitrogen
and formation of cyanamide fragment (compounds
VIIa and VIIb). Cyanamides VIIa and VIIb were also
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 4 2010

POKHODYLO et al.
558
obtained as individual substances by adding a solution
of potassium hydroxide in dimethyl sulfoxide to the
above product mixture (VI/VII). Compound VIb was
synthesized independently by cyclization of azide IV
with ethyl acetoacetate and subsequent treatment of
acid VIII with sodium azide and triethyl orthoformate
in acetic acid. We failed to convert compound IV into
4-azidoaniline, for the latter decomposed on heating in
mineral acid.
2.56 s (3H, CH3), 7.94 d (2H, m-H, J = 8.6 Hz), 8.20 d
(2H, o-H, J = 8.6Hz), 10.19 s (1H, 5″-H). Mass spec-
trum: m/z 272 [M + H]+. Found, %: C 48.77; H 3.34;
N 35.90. C11H9N7O2. Calculated, %: C 48.65; H 3.56;
N 36.04. M 271.24.
3(4)-(1H-Tetrazol-1-yl)anilines IIIa and IIIb
(general procedure). 3- and 4-Nitrophenyltetrazoles
were reduced to amino derivatives IIIa and IIIb as fol-
lows. A mixture of 51.8 g of iron powder and 311 ml
of water (or 3:1 ethanol–water mixture) was heated
under stirring, 6.2 ml of concentrated hydrochloric
acid was added, and 0.2 mol of 3- or 4-nitrophenyl-
tetrazole was slowly added. The mixture was heated
for 8 h and quickly filtered while hot. The filtrate was
cooled, and the precipitate was filtered off and purified
by recrystallization.
Azides Va and Vb reacted with cyanoacetanilide at
room temperature at a very high rate (in 2–3 s) to give
compounds IXa and IXb in high yield. The tetrazole
ring remained intact in this reaction. It is difficult to
distinguish compounds having a tetrazole ring and
1
cyanamide derivatives by H NMR spectroscopy, for
signals from the CH proton in the tetrazole ring and
from the NH proton in the cyanamide fragment are
located in the same region (δ ~10 ppm). However, the
signal from the cyanamide proton is slightly broadened
due to tautomerism. The 5-H proton in the tetrazole
ring resonates at δ 10.15–10.20 ppm. The products
were identified by mass spectrometry (chemical
ionization).
Azides IV, Va, and Vb (general procedure). A so-
lution of 0.05 mol of amine Ic, IIIa, or IIIb in 19 ml
of concentrated hydrochloric acid was cooled to 0°C,
and a cold solution of 3.45 g of sodium nitrite in
a minimal amount of water was added dropwise under
stirring. The mixture was stirred at 0–5°C, filtered
(if necessary), and cooled to –5°C, and a solution of
3.25 g of sodium azide in 10 ml of water was slowly
added dropwise under stirring, maintaining the tem-
perature below 7°C. The mixture was stirred for 2 h at
room temperature, and the product was filtered off,
washed with ice water until neutral reaction, and dried
in a dark cold place.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Varian
Unity 400 spectrometer (400 MHz) from solutions in
DMSO-d6 using tetramethylsilane as internal refer-
ence. The mass spectra (chemical ionization) were
obtained on an Agilent 1100 LC/MSD system.
N-(4-Azidophenyl)acetamide (IV). Yield 88%,
1
mp 116–117°C. H NMR spectrum, δ, ppm: 2.03 s
1-Substituted 1H-tetrazoles II, IIIa, IIIb, and
VIb (general procedure) [11]. Acetic acid, 40 ml, was
added under stirring to a suspension of 0.05 mol of
aniline Ia–Ic or VIII and 3.9 g of sodium azide in
25 ml of triethyl orthoformate, and the mixture was
heated for 4 h at 95–100°C. The mixture was cooled,
treated with 7 ml of concentrated hydrochloric acid,
and filtered, the filtrate was evaporated under reduced
pressure, and the residue was recrystallized from
ethanol.
(3H, CH3), 6.96 d (2H, m-H, J = 8.8 Hz), 7.60 (2H,
3
o-H, J = 8.8 Hz), 9.86 s (1H, NH). Mass spectrum:
m/z 177 [M + H]+. Found, %: C 54.37; H 4.70;
N 31.68. C8H8N4O. Calculated, %: C 54.54; H 4.58;
N 31.80. M 176.18.
1-(3-Azidophenyl)-1H-tetrazole (Va). Yield 73%,
mp 99–100°C. Mass spectrum: m/z 188 [M + H]+.
Found, %: C 44.78; H 2.75; N 52.07. C7H5N7. Calcu-
lated, %: C 44.92; H 2.69; N 52.39. M 187.16.
N-[4-(1H-Tetrazol-1-yl)phenyl]acetamide (II).
Yield 79%, mp 223–224°C. Mass spectrum: m/z 204
[M + H]+. Found, %: C 53.16; H 4.24; N 34.12.
C9H9N5O. Calculated, %: C 53.20; H 4.46; N 34.47.
M 203.20.
1-(4-Azidophenyl)-1H-tetrazole (Vb). Yield 83%,
mp 125–126°C. Mass spectrum: m/z 188 [M + H]+.
Found, %: C 45.10; H 2.53; N 52.03. C7H5N7. Calcu-
lated, %: C 44.92; H 2.69; N 52.39. M 187.16.
1,2,3-Triazole-4-carboxylic acids VIIa, VIIb, and
VIII (general procedure). a. A solution of 0.3 g of
metallic sodium in 5 ml of anhydrous ethanol was
cooled, 0.01 mol of ethyl acetoacetate was added, and
5-Methyl-1-[4-(1H-tetrazol-1-yl)phenyl]-1H-
1,2,3-triazole-4-carboxylic acid (VIb). Yield 81%,
mp 243–244°C (decomp.). 1H NMR spectrum, δ, ppm:
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 4 2010

SYNTHESIS AND TRANSFORMATIONS OF 1-(AZIDOPHENYL)-1H-TETRAZOLES
559
at room temperature until a solid precipitated, and the
product was filtered off.
0.01 mol of azide IV, Va, or Vb was slowly added on
cooling with ice water. The mixture was kept for
30 min in an ice bath, slowly heated to the boiling
point, and kept boiling over a period of 1 h. Hot water
was added to the precipitate until it dissolved com-
pletely (15–20 ml), or a solution of NaOH was added
to pH 11–12, and the mixture was heated for 10 min
more at the boiling point. The hot solution was poured
into 10 ml of concentrated hydrochloric acid and was
left to stand for crystallization. The precipitate was
filtered off, washed with a small amount of water on
a filter, and recrystallized from appropriate solvent.
5-Amino-1-[3-(1H-tetrazol-1-yl)phenyl]-
N-phenyl-1H-1,2,3-triazole-4-carboxamide (IXa).
1
Yield 73%, mp 194–195°C. H NMR spectrum, δ,
ppm: 6.67 s (2H, NH2), 7.04 t (1H, p-H, J = 7.6 Hz),
7.27 t (2H, m-H, J = 7.6 Hz), 7.83 d (2H, o-H, J =
7.6 Hz), 7.75 t (1H, 5′-H, J = 8.0 Hz), 7.89 d (1H,
4′-H, J = 8.0 Hz), 8.18 d (1H, 6′-H, J = 8.0 Hz), 8.53 s
(1H, 2′-H), 10.02 s (1H, NH), 10.15 s (1H, 5″-H).
Mass spectrum: m/z 348 [M + H]+. Found, %: C 55.10;
H 3.70; N 36.05. C16H13N9O. Calculated, %: C 55.33;
H 3.77; N 36.29. M 347.34.
b. Compounds VIIa and VIIb were also obtained
by treatment of the reaction mixture (after keeping for
30 min without heating) with a solution of 1.8 g
(32 mmol) of KOH in 5 ml of DMSO. The mixture
was kept for 3 h, diluted with water, and acidified. The
products were isolated and purified according to the
procedure described above in a.
5-Amino-1-[4-(1H-tetrazol-1-yl)phenyl]-
N-phenyl-1H-1,2,3-triazole-4-carboxamide (IXb).
1
Yield 89%, mp 239–240°C. H NMR spectrum, δ,
ppm: 6.69 s (2H, NH2), 7.02 t (1H, p-H, J = 7.6 Hz),
7.27 t (2H, m-H, J = 7.6 Hz), 7.84 d (2H, o-H, J =
7.6 Hz), 7.91 d (2H, 3′-H, 5′-H, J = 8.4 Hz), 8.19 d
(2H, 2′-H, 6′-H, J = 8.4 Hz), 10.02 s (1H, NH), 10.17 s
(1H, 5″-H). Mass spectrum: m/z 348 [M + H]+. Found,
%: C 55.48; H 3.64; N 36.18. C16H13N9O. Calculated,
%: C 55.33; H 3.77; N 36.29. M 347.34.
1-[3-(Cyanoamino)phenyl]-5-methyl-1H-1,2,3-
triazole-4-carboxylic acid (VIIa). Yield 53%,
1
mp 191–192°C. H NMR spectrum, δ, ppm: 2.55 s
(3H, CH3), 7.12 t (1H, 5-H, J = 8.0 Hz), 7.19 d (1H,
4-H, J = 8.0 Hz), 7.79 d (1H, 6-H, J = 8.0 Hz), 8.29 s
(1H, 2-H), 9.86 s (1H, NH). Mass spectrum: m/z 244
[M + H]+. Found, %: C 54.20; H 3.59; N 28.63.
C11H9N5O2. Calculated, %: C 54.32; H 3.73; N 28.79.
M 243.22.
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